1. ^*Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, U.S.A.
2. ^†Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
3. ^‡Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
4. ^§Shriners Hospitals for Children-Northern California, Sacramento California and Department of Surgery, University of California, Davis, California, U.S.A.

Correspondence: Dr Nancy Ratner, Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati, College of Medicine, PO Box 670521, Cincinnati, OH 45267, U.S.A.

Received 15 December 1998; Revised 26 February 1999; Accepted 7 March 1999.

Abstract

Neurofibromatosis type 1 patients develop peripheral nerve tumors (neurofibromas) composed mainly of Schwann cells and fibroblasts, in an abundant collagen matrix produced by fibroblasts. Trauma has been proposed to trigger neurofibroma formation. To test if loss of the neurofibromatosis type 1 gene (Nf1) compromises fibroblast function in vivo following trauma, skin wounding was performed in Nf1 knockout mice. The pattern and amount of collagen-rich granulation bed tissue, manufactured by fibroblasts, was grossly abnormal in 60% of Nf1+/– wounds. Nf1 mutant fibroblasts showed cell autonomous abnormalities in collagen deposition in vitro that were not mimicked by Ras activation in fibroblasts, even though some Nf1 effects are mediated through Ras. Nf1+/– skin wound fibroblasts also proliferated past the normal wound maturation phase; this in vivo effect was potentiated by muscle injury. In vitro, Nf1+/– fibroblasts showed higher proliferation in 10% serum than Nf1+/+ fibroblasts. Macrophage-conditioned media or epidermal growth factor potentiated Nf1+/– fibroblast proliferation in vitro, demonstrating abnormal response of mutant fibroblasts to wound cytokines. Thus Nf1 is a key regulator of fibroblast responses to injury, and Nf1 mutation in mouse fibroblasts causes abnormalities characteristic of human neurofibromas.